Malignancy Answers

Cancer

1. Avoiding smoking, eating fruit and veg, maintaining a healthy weight, drinking less
alcohol, being sun smart, eating more fibre (prevents colorectal), eating less
processed meat and salt, being active.

2. Avoiding long term use of HRT, breast feeding if possible, avoiding radiation eg x-
rays, avoiding infections and minimising work risks (asbestos, benzene, leather dust,
wood dust, naphylamine, vinyl chloride).

3. a) breast, melanoma, testicular, prostate, hodgkins lymphoma, uterus.

b) pancreas, brain, lung, oesophagus, stomach, myeloma.

4. Benign- local growth, encapsulated in a fibrous rim, cohesive, cannot metastasise,

slow growth, no necrosis or ulceration, very poor vasculature
Malignant- fast growth, cells can metastasise, no obvious border between healthy
cells and the tumour, frequent recurrence, necrotic and ulcerative, vascularity.

5. Normal- single nucleus, large cytoplasm, fine chromatin.

Cancer- more than one or a large nucleus, small cytoplasm, irregular shape and
disorganised arrangement, multiple nucleolus and coarse chromatin.

6. Metastasis is where cells enter blood stream and lymph and migrate to other tissues
and then grow in a suitable environment. Eg. Prostate cancer metastasises to the
pelvic bone, breast cancer to the lymph and lymph nodes. Gliomas rarely
metastasises due to the BBB.

7. Colorectal cancer starts as an adenoma (growth of cells) due to the APC mutation, K-
ras mutation promotes growth of this adenoma. This then becomes carcinogenic
(adenocarcinoma) due to the TP53 mutation and eventually metastasises due to the
PRL3 gene amplification. This process takes about three years so screening this often
is effective either to catch adenoma cells or adenocarcinoma cells.

8. Cigarette smoke contains chemicals such as arsenic, benzene, cadmium, nickel,

napthylamine. These can initiate a series of genetic mutations to cause canceropus
cells but this usually takes a few decades.

9. Viral genetic information is carried in nucleic acids and inserted into DNA of infected
cell, this can cause the cell to become malignant. (Eg. Epstein barr virus- Burkitts
lymphoma, HPV- cervical cancer, Hep B- Liver cancer, t-call lymphotropic virus- t-
cell leukaemia) Bacteria such as H.pylori has been known to increase risk of stomach
cancer due to the ulcers it causes.

10. Xeroderma pigmentosum- skin cancer

 Wilms tumour- kidney
Familial adenomatous polyposis- colon, rectum
BRCA1/2- Breast/Ovary

11. Controlled by cyclins which bind to cyclin dependant kinases to phosphorylate

proteins and move on to the next stage, these cyclins are inhibited by p21 protein.
P21 is controlled by a protein coded for by oncogenes and tumour suppressor gene
(p53). Specifically G1 into S is regulated by a tumour suppressor pRB.

Mitosis is initiated by cyclin B (cdk1), g1 is initiated by cyclin D (cdk2,4,5), S is

initiated by cyclin E (cdk2) and g2 is initiated by cyclin A (cdk2)

12. Proto-oncogene damage, tumour suppressor gene damage, programmed cell death
genes, genes involved in DNA repair.

13. Proto-oncogenes code for growth factor, growth factor receptor, cytosolic and
nuclear transducers. This promotes cell proliferation. Where there is a translocation
this can cause the protooncogene to become an oncogene and affects the regulatory
mechanism so there is excess growth. Amplification of the protooncogene then
causes it to be an oncogene since this causes excess growth. A point mutation can
cause hyperactivity of the gene or degradation resistance. Eg. RAS gene involved in
signal transduction. If this is mutated it wont depend on growth factors.

14. Tumour suppressor genes eg. P21, p53 and pRb are required to regulate the cell
cycle. If these are lost there will be excess growth and division and also growth of
damaged cells.

15. Mismatch repair-

Nucleotide excision repair
Recombination repair

16. ER positive breast cancer- proliferation controlled by the binding of estrogen to the
ER. Treated with ER receptor blockers eg. Tamoxifen or treated with aromatase
inhibitors to prevent the conversion of androgens to estrogen.
HER2 positive breast cancer- HER2 gene over expression causing over production of
HER2 proteins (which signals cells to grow and divide). This can be treated with a
monoclonal antibody against the HER2 protein (Herceptin). Meaning that the two
part of the HER2 receptor cannot come together there is then no
autophosphorylation and no signalling. It also tells the body immune system to
target this cell
Triple negative breast cancer- aggressive form and doesn’t have specific protein
targets there for general cytotoxics must be used which causes side effects in the GI
and also causes alopecia. This can be used before or exclusive to an operation.

17. Targetting of fast growing cells  myelosuppression and hence

immunosuppression, alopecia and GI side effects (mucositis)
18. Treatments are non-specific
Cancers are heterogenous
Cancers can develop resistance – efflux (via p-glycoprotein), tolerance of adducts,
repair of adducts, deactivation by intracellular glutathione, toxicity to normal cells.

19. Alkylators- gets rid of a chlorine leaving a free carbonium ion this allows it to join an
alkyl group to the no7 nitrogen on the purine ring of the guanine base. This causes
cross lining between guanines and then prevents the DNA strands from unwinding.
Carmustine, melphalan

Platinums- similar to the previous MoA, but do not have an alkyl group, the platinum
binds to the no7 N atom and causes cross linkage to the other guanines and then
prevent unwinding
Cisplatin- standard structure
Carboplatin has bidentate dicarboxylase instead of the chlorine
Satraplatin is an oral formulation

Intercalating agents (anthracycline based)- based off of an antibiotic, planar rings

bind to the hydrophobic faces of the DNA and cause localised unwinding of DNA

Actinomycin- inhibits transcription by binding to DNA at the transcription initiation

complex preventing transcription by RNA

Spindle poisons-
Vinca alkaloid spindle poisons eg. vincristine bind to tubulin dimers and prevent the
aggregation of the tubule there for they don’t have the strength to pull apart
Taxanes eg. taxol (paclitaxel) stabalises mictrotubules and therefore cannot shorten
to pull the cells apart

Antimetabolites- false substrate or inhibit the enzyme involved in the synthesis or

uptake
Cancer cells make new bases when making DNA but normal cells recycle bases.
Anti-purines inhibits purine synthesis by preventing synthesis of GMP so the DNA
cannot be made. Eg. mercaptopurine, 6-thioguanine
Antipyridines will act as a substrate for the thylidimilate synthase enzyme and cause
apoptosis, will also be used in the formation of RNA mistakenly and alter protein
synthesis. Egt. 5-fluorouracil
Anti-folates prevents utilisation of folic acid by cells by binding to the folic acid
receptor (dihydrofolatereductase). Eg, methotrexate

20. Provides carbon groups to be used to synthesise purine or pyrimidine bases. The
folate must be reduced to dihydrofolate and then to tetrahydrofolate, in the
absence of folate uptake (ie. Methotrexate use) dUMP to TMP results in the normal
yield of dihydrofolate but since DHFR is inhibited then tetrahydrofolate cannot be
produced and hence the DNA cannot be created.

21. Combining with molecular targets eg. biologics

 Increased delivery eg. via liposomes
Given with platinum resistance modulators eg. TLK286 and decitabine
Oral formulations eg Satraplatin

22. Given with a combination drug called FOLFOX (containing fluorouracil and folinic
acid)
23. Nociceptive Pain- by inflammation (dull gnawing)
Pathological or neuropathic pain- nerve damage and usually chronic (burning or
shooting)
Psychological pain- in depression and anxiety eg. back pain and headaches

24. Step 1- non opioid(s) with or without an adjuvant

Step 2- weak opioid with or without non opioid and adjuvant (low dose cocodamol
not much more beneficial than paracetamol but provides room for addiction and
dependence and falls and confusion in the elderly)
Step 3- strong opioid with or without non opioid and adjuvant.

25. Binds to an inhibits cox which means arachidonic acid cannot be a substrate to
produce prostaglandins. Cox 2 associated with production of prostaglandins (PGE-
stomach lining and vasodilation, PGI- aka. prostacyclin reduced platelet aggregation,
PGA- aka thromboxane responsible for platelet aggregation, this is in balance with
PGI) but there is not a drug which inhibits only this. COX 2 more associated with
cardiac toxicity since there’s an imbalance between thromboxane and PGI and blood
becomes more clotty.

26. Drugs which are used but not for their primary purpose. Tricyclics, Anti-epileptics,
SNRIs, alpha blockade, irritants and cannabinoids. These are used mainly for
neuropathic pain and can be used at any stage in the WHO ladder. Amitriptyline
most common at 10-50mg per day, gabapentin next most common and needs to be
slowly titrated.

27. Receptors, genes, angiogenesis and metastasis, microenvironment and antigens

which are unique to cancer cells or more expressed.

28. Goal- determine what drug to use when to use it and at what does to achieve early
diagnosis, optimal treatment, avoid adverse effects and prevent unnecessary cost
from failure of clinical trials.
Done via proteonomics (mass spectrometry) and genomic screening (microarray)

29. Predisposition (disease related biomarker), presence (diagnostic biomarker),

determination of effectiveness of the drug (drug-related biomarker), what dose to
give (pharmacodynamic biomarker), prediction of toxicity. An example of a
biomarker being PSA in prostate cancer when levels are low the cancer is being
treated if levels rise again treatment is beginning to fail. Also, radiation is always
given at low dose due to 5% of the population being sensitive, if we could test for
the sensitivity then everyone else could be treated at high dose. Also BRCA 1
screening, HER-2 receptor presence,
30. Translocation between chromosome 22 (BCR) and chromosome 9 (ABL)- translation
into a very active tyrosine kinase.
Treatment with imatinib- inhibits the Ph chromosome kinase so it cannot be
phosphorylated and hence cannot carry out its function. Problems with this include
the fact that it can cause organ stress which presents as a rash on the hands-
treatment then needs to be stopped for a while. The tyrosine kinase can mutate so
that the drug cannot bind, there is also a drug called nilotinib for tighter binding.

31. Increased expression of TK receptor and its ligand

Mutation altering autoregulation of TK
Fusion with a partner protein which  activation of TK.

32. Growth factors have three domains- external ligand binding domain,
transmembrane protein, cytoplasmic tyrosine kinase domain
GFRs receptors have two dimers when a ligand binds these dimers come together
and this results in autophosphorylation. The autophosphorylation by TK results in
adapter protein pathway which leads to activation of RAS causing downstream
signalling to the nucleus to cause proliferation. These dimers can be permanently
dimerised and can contribute to the establishment of an autocrine ligand loop.

33. Extracellular- Targets growth factors: c-sis protooncogene is the gene for platelet
derived growth factor which can cause cancer and increase in this gene causes
sarcomas and glioblastomas. This is similar for granulocyte macrophage colony
stimulating factor, transforming growth factor alpha, epidermal growth factor,
fibroblast growth factor
Cetuximab is a human mouse antibody against EGF used in colorectal cancer, it
inhibits cell cycle proteins, angiogenesis, promotes apoptosis, NK cell activation and
death of tumour cells
Panitumumab is a human MAB against EGFR so good for cancers with loads of these
eg bowel cancer however not bowel cancer with KRAS

Nuclear- Antisense oglionucleotides can bind to mRNA and prevent translation

however cell thinks its a virus and gets rid of it

Intracellular- small molecule inhibitors of the TK domains called anilinoquinazolines

(gefitinib and erlotonib) this is the best was by far as it is small molecule and can get
deep into the tumour.
These work better on non small cell lung cancer tumours with EGFR TK anti
apoptosis mutations. Adenocarcinoma is the main type that harbours these
mutations and is more common in women, Asians and non smokers. Resistance is
developed 8-12 months after start of treatment. They cause radiosensitivity.
Novartis- parental pyrrolopyrimidine
Response rates are low due to genetic polymorphisms of EGF receptors, varied
metabolism, ubiquitination.
34. Important since oncogenic- RAS codes for a small mw g-protein called p21ras. RAF
codes for a protein kinase called Raf. The RAS gene is mutated in 10-20% of cancer
patients. The mutation results in encoding a form of p21ras that is constituitively
active in a GTP bound state and doesn’t return to an inactive form like that of normal
RAS. K-RAS, H-RAS, N-RAS cycle between inactive and active forms by GTP binding
and GDP binding. It is TKs and Gprotein coupled receptors which activate ras and
lead to the stimulation of the raf-MEK-MAP pathway. GTPase-activating proteins
usually inactivate RAS however in tumours point mutations prevent this eg. Gly12 to
ASP. Raf is a kinase which when b-mutated is always activated.

35. CAR-T therapy involves removing white blood cells from the cancer patient and
engineering them to be active against cancer by inserting the chimeric antigen
receptor gene. Then they are administered to the patient. This is very difficult as
cells usually reject things and it costs as has to be done in sterile conditions. Will be
used to treat childhood cancer.

36. Tumour would be removed and then blasted with radiation and DNA removed and
then injected back into the patient

37. The body has immune tolerance and therefore does not illicit a response to its own
cells. Cancer is a disease of the bodys own cells therefore a malignancy would not be
recognised. Cancer vaccine only applicable to a small number of diseases.

38. Radioimmunotherapy is where an antibody is injected into a person with a

radioactive molecule attached this allows the radiotherapy to be targeted directly at
the target cells and avoids unwanted exposure, however the cells must have a
specific antigen which can be targeted.

39. Dendritic cell therapy can work in two ways. Either the tumour DNA can be inserted
into the patient a viral vector allowing the dendritic cells to uptake this and then
display the antigens of this tumour or tumour antigens can be injected directly into
the dendritic cell and harvested out with the body, then they. Can be inserted back
into the patient and the dendritic cells will display these antigens.

40. BCG therapy is a vaccination therapy used in the treatment of bladder cancer. The
mechanism of anti-tumour is unclear as yet however the attenuated live bacteria
potentiate a t-helper cell respose.

41. PD-1 proteins are present on the outside of cancer cells and act as a masking tool so
that t-cells cannot detect the cancer cell. They bind to the t-cell and hold it too far
out from the cancer cell. Inhibitors inhibit the receptor on the t cell and unmask the
cancer cell allowing detection destruction. The inhibitors are antibodies and have
revolutionised the treatment for melanoma. (pembrolizumab)

42. CHOP therapy- cyclophosphamide, hydroxydaunorubicin (Adriamycin), oncovin

(vincristine), prednisone. Side effects should not cross over should be a mix of all
side effects. Could possibly add rituximab.
 FOLFIRNOX- folinic acid, 5-fluoruracil (anti-pyrimidine), irinotecan, oxaliplatin.
TPT-MIBG- topotecan (topoisomerase inhibitor) combined with MIBG to increase the
sensitivity to MIBG by preventing DNA repair. Works exceptionally well when given
at the same time. This can cause myelosuppression so a bone marrow transplant is
usually necessary. And is given with KI (to protects thyroid) and hyperbaric O2
(sensitisation)

43. Apoptosis, mutation, delay the cell division, carcinogenic phenotype changes,
reproductive failure.

44. Radiosensitisers increase a cells susceptibility to damage by radiation. Radiation can

only work in cells which aren’t hypoxic so that the oxygen can form damaging free
radicals. If. Cells are hypoxic then these free radicals cannot be formed sometimes
drugs are given which act as oxygen like molecules.

45. Radiation can have many effects on cells especially cancer cells. Sometimes the DNA
is damaged but the cancer cells are good at repairing this damage however this
repair is often flawed- leading to a mutation also the cancer cells upregulate
antiapoptotic genes and survival genes. Therefore the radiation must be given in
combination with a drug that impairs this repair.
Radiotherapy can cause cytotoxicity to normal cells so we want to target certain cells
to do this we can give it intraoperatively or we can do it by giving the radiation in a
form which is attracted to certain cells, eg. sodium iodide isotope is good for thyroid
cancer as the thyroid cells are looking to uptake iodine. Or neuroendocrine cancers,
add an adrenaline like molecule onto the radionuclide.

46. Apoptosis
Complement dependent
Antibody dependent
Vaccine like effects- adaptive immunity against cells that may survive the initial blast.

47. The radionuclide is produced using elements with an atomic number less than
bismuth and two stable isotopes. They are either neutron deficient (proton
accelerator) or proton deficient (nuclear reactor). It is stored in a radiopharmacy
under appropriate conditions and also dispensed my a radiopharmacist. It is
administered to a patient in a lead lined room to prevent exposure to other people.
The patient remains radioactive for 4 days.

48. Self- suffiency- relates to oncogenes and the facts that cancer can create its own
growth signals, activate later in the pathway and also increase receptor expression

Insensitivity to negative signals- Essentially tumour suppression. Rb active when not

phosphorylated. Mutation which causes permanent phosphorylation so cells bypass
even if they are bad.
 Evasion of apoptosis- Two main pathways TNF alpha extrinsic or the mitochondrial
pathway TNF binds and then DISC pathway is activated caspase 8 is released and
then cascade causes cell death. The caspase 8 also cleave proapoptotic protein and
activates the mitochondrial pathways. Apoptosis is initiated by p53- this also
distrupts cell cycle and c auses cell cycle arrest when DNA is damaged. Absence of
this or a mutation in p53 leads to anti-apoptosis and hence the growing of damaged
cells.

Limitless proliferation- expression of telomerase meaning infinite amount of

telomeres and endless division

Angiogenesis- cancer cells cannot survive without a blood supply for oxygen and
nutrients. The cancer cells release growth factors such as VEGF when there is
hypoxia to grow blood vessels these are usually disorganised leaky and chaotic. We
can inhibit these growth factors however timing must be considered as no blood
supply= no drugs can get there.

Invasion and metastases- immunoglobulins and cadherins bind cells to other cells
and integrins bind this to an extracellular matrix. This creates a tightly packed
environment and it is hard for cells to escape however cancer cells express n-
cadherins which can sneak to the blood vessel and digest the wall it then releases
metalloproteases and collagenase and stromolysin to break down the matrix and
allow other cells to escape.

Arthritis
1. Genetic susceptibility, exogenous arthritogen, autoimmune reaction to the joint
components, expression and production of mediators of joint damage.

2. CD4 t-cell recruitment  b-cell activation: rf factor and joint injury. Macrophage
activation: cytokine release and then fibroblasts, chondrocytes and synovial cells
created leading then to release of collagenase, stromelysin, elastase and
proliferative synovitis.
Ultimately causing pannus formation which fuses and destroys the joints. Typically
four joints are involved before a diagnosis is made.

3. Joint pain and swelling (synovitis), stiffness following inactivity, flu-like symptoms,
boggy joints. Other features such as: changes in muscle, skin, blood vessels and
lungs.

4. Number of joints affected, type of joint involved, skin, nails, eyes, mouth, genitilia
 5. Many active joints, high ESR or CRP at outset, rf factor, early sign of erosion, poorer
score of function, Anti- CCP.

6. Number of swollen joints, ESR, global assessment of global health /10. >5.1- active
disease and eligible for biologics. <3.2- well controlled and <2.6- remission. This
score doesn’t include the feet.

7. X-rays for soft tissue damage, joint narrowing and erosions

USS: good for synovial swelling and erosions

8. Thickened, new blood vessels and very high white blood cell count

9. First to last line:

NSAIDs- first line and fast acting

Corticosteroids- more potent anti-inflammatory effects. Can be a direct injection into the
joints in severe cases. Usually used to bridge treatment which
DMARDs- eg methotrexate, sulfasalazine, leflunomide, hydroxychloroquine (also IM gold
and penicillamine)
Biologics- target TNF alpha eg. infliximab, etanercept, adalimumab
Alternatives- abatacept (inhibits activation of lymphocytes but not approved), rutiximab
(kills specialised b-cells).

10. Proinflammatory mediator by producing cytokines, expression of adhesion

molecules and growth stimulation.
Plays a key role in acute and chronic inflammation, anti-tumour and infection.
Comes in two forms – TNF1 which is a membrane bound form and is 26k Da, can be
converted to the soluble form TNF2 which is 17k Da by TACE
The receptors have different pathways
TNF1 receptor (50-60k Da) recruits TRADD which induces apoptosis
TNF2 receptor (75-80k Da) recruits TRAF2 and induces the NFkB pathway- this leads
to expression of adhesion molecules, increased IL-1, increased cytokines and
prevents apoptosis.

11. TNF molecules, TNF receptors, TACE, NFkB, SAP kinase and MAP kinase pathways.

12. Infliximab is an antibody against TNF alpha it can bind preventing receptor binding. It
can also cause phagocytosis of the TNF producing cells as it forms complex
activation- Complex protein binds to phagocyte and antibody which is bound to a tnf
which will be near the producing cell. Phagocyte engulfs this.

13. Splits into 5-ASA and sufapyridine in the colon. 5-ASA is the active component and
blocks production of prostaglandins and leukotrienes. It also inhibits bacterial
peptide induced neutrophil chemotaxis and adenosine secretion. It scavences
reactive oxygen metabolites and inhibits NFkB activation. Its given at a dose of
3mg/kg and the same dose two weeks following and 6 weeks following and
 thereafter 8 weekly. Use of this increases infection risk and risk of lupus. Body can
also create HAMA against it- reduced in immunosuppressants.

14. The patients must have access to specialist in the event of a flareup and also mDT
team.
Must remain under care of a rheumatologist for as long as they are on treatment.
Must be treated aggressively until the target has been reached.
Blood monitoring- FBC, LFTs, U&Es, CRP this is done two weekly then monthly then
six weekly then twelve weekly and can be done more often if patient is at risk of
toxicity.

15. Biologics aim to restore the balance of cytokines and each biologic has its own
cautions but all cause immunosuppression and often in RA patients they are immune
suppressed already.